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Four novel mutations in the cystathionine β-synthase gene: Effect of a second linked mutation on the severity of the homocystinuric phenotype
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Four novel mutations in the cystathionine β-synthase gene: Effect of a second linked mutation on the severity of the homocystinuric phenotype
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Four novel mutations in the cystathionine β-synthase gene: Effect of a second linked mutation on the severity of the homocystinuric phenotype
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Journal Article
Four novel mutations in the cystathionine β-synthase gene: Effect of a second linked mutation on the severity of the homocystinuric phenotype
1999
Overview
Homocystinuria due to cystathionine β‐synthase (CBS) deficiency is frequently caused by missense mutations. In this article, we report four novel missense mutations in the CBS gene: 172C→T (R58W) linked in cis with A114V; 376A→G (M126V); 904G→A (E302K); and 1006C→T (R336C). The CBS activity of the corresponding mutant enzymes expressed in Escherichia coli was greatly diminished, confirming the pathogenicity of these mutations. Western analysis showed that the R58W+A114V and M126V mutant enzymes were unstable in E. coli, while the E302K subunits were partially degraded to shorter products. Using site‐directed mutagenesis we found that CBS containing either the R58W or A114V as the only mutations demonstrated 18% and 46% of normal activity, respectively. Both mutant forms of CBS were stable in E. coli. When these two mutations were expressed in cis, the resultant mutant protein exhibited activity 1.3% that of a control. All these in vitro results were in good agreement with the clinical manifestation in these patients. The Italian patient 2241, an A114V+R58W/M126V compound heterozygote, exhibited severe pyridoxine nonresponsive homocystinuria, while another Italian patient 2242, with an A114V/E302K genotype, responded to pyridoxine treatment and had a much milder phenotype. The third patient 3064, an English compound heterozygote for two severe mutations R336C and G307S, was B6 nonresponsive. This report of a ninth homocystinuric allele carrying two mutations in cis raises the possibility that double mutant alleles may be underestimated in homocystinuric patients. In this context, a search for additional mutations in cis may sometimes be necessary to establish a good genotype‐phenotype relationship. Hum Mutat 13:453–457, 1999. © 1999 Wiley‐Liss, Inc.
Publisher
John Wiley & Sons, Inc
Subject
